The central aim of this project is to resolve the relationship between beta-gene cluster haplotypes and the phenotypic expression of sickle cell anemia patients. Although there is considerable evidence that the haplotypes are strongly linked to the expression of Ggamma, their linkage to the expression of HbF is present, but considerable variation within haplotypes exist. This variability can stem from two origins: a) presence of other genetic determinants, as for example an X-link factor; or b) the presence of polymorphism within each haplotype that generates variability. this project attempts to explore the first issue, by doing correlations between haplotypes and hematological an clinical parameters with proper concern for gender influence. For this purpose we have put together a large data base from which to draw this information, that includes the U. of Georgia and the U. of Mississippi. To address the second problem, we will pursue two interesting leads: a) we will explore the presence of polymorphic sequences in site known to affect the expression of the beta-gene, hypersensitivity site 2 and enhancer regions 3' to the Agamma gene; b) We will look for polymorphism in the amounts of regulatory proteins capable of binding (AT) repeat region 5' of the beta-gene and in the -158 site 5' to the Ggamma gene. To accomplish these aims we will use not only DNA sequencing, and gel-shift assays but also a transgenic mice model utilizing our Central Transgenic Mice facility at the Albert Einstein College of Medicine. At a minimum this project will establish with authority the correlation between beta-gene cluster haplotypes and the phenotypic expression of sickle cell anemia, including its relationship to anemia (and hemolysis), major organ damage and incidence of painful crises. It has, on the other hand, the potential of illuminating the molecular basis for the variation within haplotypes in the expression of HbF among these patients. In the process, we might significantly increase our knowledge about the genetic regulation of HbF expression in general.